HIV establishes infection in lung during acute infection. However, virus replication appears to be controlled after acute infection, and HIV interstitial pneumonia does not develop until the late stages of infection prior to the development of AIDS. The goals of these studies are to elucidate the mechanism that regulates acute HIV/SIV replication in the lung and cells in the bronchoalveolar lavage and to establish a testable model for control of HIV/SIV replication in the lung. Using an SIV/macaque model of HIV pneumonia in which all infected animals develop interstitial pneumonia and AIDS by 3 months, we demonstrated that there is viral replication in the lung during acute infection that is controlled during the asymptomatic infection, but virus replication resurges during the late stages of disease when there are lymphocytic infiltrates in the lung and pneumonia. Because active virus replication continued in the periphery during this time, these findings suggested the existence of a mechanism in the lung that mediates down-regulation of acute HIV/SIV replication. Alveolar macrophage is the predominant cells in the lung productively infected with HIV/SIV. Because HIV replication in macrophages requires C/EBP sites in the HIV LTR, we considered the possibility that negative regulation of C/EBP-dependent transcription is integral to the mechanism suppressing acute HIV/SIV replication in the CNS. Consistent with this notion is the ability of IFNbeta to inhibit active HIV transcription via induced expression of a dominant-negative isoform of C/EBPbeta. Based on preliminary studies demonstrating up-regulated expression of IFNbeta and the dominant-negative isoform of C/EBPbeta in the lung, our hypothesis is that acute virus replication in the lung is controlled by IFNbeta and increased expression of the dominant-negative form of C/EBPbeta in macrophages. Resurgent virus replication in the lungs during terminal disease is the result of increased influx of CXCR3+/CD8+ cells, decreased inhibition by the dominant-negative form of C/EBPbeta protein due to and increased activation of NF-kappaB in macrophages. Intervention with exogenous IFNbeta during asymptomatic infection will inhibit influx of CXCR3+ CD8+ cells, maintain the control of HIV transcription by the dominant-negative form of C/EBPbeta protein and inhibit resurgent virus activation in the lung and the development of associated lesions. These studies will be supported by our collaborators, Dr. William Bishai, an expert in AIDS and M. tuberculosis, in humans, and Dr. Christopher Karp, an immunologist who has studied HIV and Multiple Sclerosis and is actively involved in therapeutic treatment of MS patients in INFbeta.